Shi Xiaoying, Shen Tianyi, Gu Muge, Guan Yuanye, Aimaiti Gulizeba, Yu Wei, Zhang Xiangqi, Yuan Wei-En, Su Jing
Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China; Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, and School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai 200240, China; Inner Mongolia Research Institute of Shanghai Jiao Tong University, China.
Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China; Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, and School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai 200240, China; Inner Mongolia Research Institute of Shanghai Jiao Tong University, China.
J Colloid Interface Sci. 2025 Oct 15;696:137904. doi: 10.1016/j.jcis.2025.137904. Epub 2025 May 15.
The tumor microenvironment (TME) impedes the effectiveness of therapeutic strategies such as chemodynamic therapy (CDT). This study presents a novel nanoscale drug delivery system designed for the precise release of the chemotherapeutic agent doxorubicin (DOX), aiming to overcome treatment limitations, reduce systemic toxicity, and enhance antitumor efficacy. Mn(III) serves as an immunomodulatory agent, while Cu(II) regulates the levels of glutathione (GSH). Layered double hydroxides (LDHs) were synthesized and efficiently loaded with DOX, followed by surface modification with hyaluronic acid (HA). The HA-coated LDH/DOX nanocarriers showed effective internalization by tumor cells and provided a pH-responsive release of DOX. In vitro, the LDH/HA/DOX complex exhibited strong catalytic activity in the Fenton reaction. In vivo studies using an H22 hepatocarcinoma model confirmed its potent antitumor activity and excellent biocompatibility. Immunohistochemical analyses revealed that treatment with LDH/HA/DOX significantly increased infiltration of M1-polarized tumor-associated macrophages (TAMs), CD4 + T cells and CD8 + T cells, while decreasing M2-polarized TAMs. This change in immune cell profile was associated with notable tumor growth inhibition.
肿瘤微环境（TME）会阻碍化学动力学疗法（CDT）等治疗策略的效果。本研究提出了一种新型纳米级药物递送系统，专为精确释放化疗药物阿霉素（DOX）而设计，旨在克服治疗局限性、降低全身毒性并提高抗肿瘤疗效。锰（III）作为免疫调节剂，而铜（II）调节谷胱甘肽（GSH）水平。合成了层状双氢氧化物（LDH）并有效负载DOX，随后用透明质酸（HA）进行表面修饰。HA包被的LDH/DOX纳米载体显示出被肿瘤细胞有效内化，并实现了DOX的pH响应性释放。在体外，LDH/HA/DOX复合物在芬顿反应中表现出强大的催化活性。使用H22肝癌模型进行的体内研究证实了其强大的抗肿瘤活性和出色的生物相容性。免疫组织化学分析显示，用LDH/HA/DOX治疗可显著增加M1极化的肿瘤相关巨噬细胞（TAM）、CD4 + T细胞和CD8 + T细胞的浸润，同时减少M2极化的TAM。免疫细胞谱的这种变化与显著的肿瘤生长抑制相关。
